EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia.

Veronika Boczonadi,Agota Princzinger,Michele Giunta,Ileana Ferrero,Yuval Cinnamon,Tuomo Polvikoski,Markus Schuelke,Orly Elpeleg,Juliane S Müller,Rita Horvath,David J Elliott,Susanne Lützkendorf,Mojgan Reza,Jennifer Munkley,Hanns Lochmüller,Angela Pyle,Jade Quartararo,Patrick F Chinnery,Luba Kalaydjieva,Veronika Karcagi,Daniel Birchall,Talya Dor,Helen Griffin,Mauro Santibanez‐Koref ,Simon Edvardson ,Henriett Pikó ,Laura Flórez

doi:10.1038/ncomms5287

Abstract

The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs (mRNAs). EXOSC8 is an essential protein of the exosome core, as its depletion causes a severe growth defect in yeast. Here we show that homozygous missense mutations in EXOSC8 cause progressive and lethal neurological disease in 22 infants from three independent pedigrees. Affected individuals have cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system or spinal motor neuron disease. Experimental downregulation of EXOSC8 in human oligodendroglia cells and in zebrafish induce a specific increase in ARE mRNAs encoding myelin proteins, showing that the imbalanced supply of myelin proteins causes the disruption of myelin, and explaining the clinical presentation. These findings show the central role of the exosomal pathway in neurodegenerative disease.

Highlights

The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs
The first human disease linked to an integral exosome component was EXOSC3 deficiency, which has been identified in pontocerebellar hypoplasia (PCH) and spinal motor neuron disease (PCH1, MIM 607596)[26,27,28]
A broader clinical spectrum was recently suggested in patients with EXOSC3 mutations including isolated cerebellar hypoplasia and spinal anterior horn involvement or intellectual disability, early-onset spasticity and cerebellar atrophy[29]

Summary

Introduction

The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs (mRNAs). Experimental downregulation of EXOSC8 in human oligodendroglia cells and in zebrafish induce a specific increase in ARE mRNAs encoding myelin proteins, showing that the imbalanced supply of myelin proteins causes the disruption of myelin, and explaining the clinical presentation These findings show the central role of the exosomal pathway in neurodegenerative disease. Many cellular RNAs that play key roles in important cellular processes such as translation (ribosomal RNAs, transfer RNAs and small nucleolar RNAs) and mRNA splicing (small nuclear RNAs) are produced as precursor molecules that are trimmed from their 30-ends by the human exosome[11] This complex organization of the exosome provides the versatility needed to cope with the huge variety of RNA substrates in the cell[12]. We report that deficiency of a core component of the human exosome leads to severe infantile overlap phenotype of psychomotor deficit, cerebellar and corpus callosum hypoplasia, hypomyelination and spinal muscular atrophy (SMA)

Methods

Results

Conclusion